Comprehensive molecular characterization of long-term glioblastoma survivors

Hao Xu; Xinyu Chen; Ying Sun; Xiaomu Hu; Xuan Zhang; Ye Wang; Qisheng Tang; Qiongji Zhu; Kun Song; Hong Chen; Xiaofang Sheng; Yu Yao; Dongxiao Zhuang; Lingchao Chen; Ying Mao; Zhiyong Qin

doi:10.1016/j.canlet.2024.216938

Comprehensive molecular characterization of long-term glioblastoma survivors

Cancer Lett. 2024 May 9:216938. doi: 10.1016/j.canlet.2024.216938. Online ahead of print.

Authors

Hao Xu¹, Xinyu Chen², Ying Sun³, Xiaomu Hu⁴, Xuan Zhang⁵, Ye Wang¹, Qisheng Tang¹, Qiongji Zhu¹, Kun Song¹, Hong Chen⁴, Xiaofang Sheng⁶, Yu Yao¹, Dongxiao Zhuang¹, Lingchao Chen⁷, Ying Mao⁸, Zhiyong Qin⁹

Affiliations

¹ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China.
² Department of Breast and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
³ GenomiCare Biotechnology (Shanghai) Co. Ltd., Shanghai, China; Department of Data Science, Shanghai CreateCured Biotechnology Co. Ltd., Shanghai, China.
⁴ Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
⁵ GenomiCare Biotechnology (Shanghai) Co. Ltd., Shanghai, China.
⁶ Department of Radiation Oncology, Huashan hospital, Fudan University, Shanghai, China.
⁷ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China. Electronic address: chenlingchao12@sina.com.
⁸ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China. Electronic address: maoying@fudan.edu.cn.
⁹ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China. Electronic address: qinzhiyong@fudan.edu.cn.

PMID: 38734160
DOI: 10.1016/j.canlet.2024.216938

Abstract

Fewer than 5% glioblastoma (GBM) patients survive over five years and are termed long-term survivors (LTS), yet their molecular background is unclear. The present cohort included 72 isocitrate dehydrogenase (IDH)-wildtype GBM patients, consisting of 35 LTS and 37 short-term survivors (STS), and we employed whole exome sequencing, RNA-seq and DNA methylation array to delineate this largest LTS cohort to date. Although LTS and STS demonstrated analogous clinical characters and classical GBM biomarkers, CASC5 (P = 0.002) and SPEN (P = 0.013) mutations were enriched in LTS, whereas gene-to-gene fusions were concentrated in STS (P = 0.007). Importantly, LTS exhibited higher tumor mutation burden (P < 0.001) and copy number (CN) increase (P = 0.013), but lower mutant-allele tumor heterogeneity score (P < 0.001) and CN decrease (P = 0.026). Additionally, LTS demonstrated hypermethylated genome (P < 0.001) relative to STS. Differentially expressed and methylated genes both enriched in olfactory transduction. Further, analysis of the tumor microenvironment revealed higher infiltration of M1 macrophages (P = 0.043), B cells (P = 0.016), class-switched memory B cells (P = 0.002), central memory CD4⁺ T cells (P = 0.031) and CD4⁺ Th1 cells (P = 0.005) in LTS. We also separately analyzed a subset of patients who were methylation class-defined GBM, contributing 70.8% of the entire cohort, and obtained similar results relative to prior analyses. Finally, we demonstrated that LTS and STS could be distinguished using a subset of molecular features. Taken together, the present study delineated unique molecular attributes of LTS GBM.

Keywords: DNA methylation array; Glioblastoma; RNA sequencing; long-term survivor; mutation analysis.